[F31] Role of Synaptogyrin-3 in Methamphetamine Self-Administration and Dopamine Dysfunction
Ente: National Institute on Drug Abuse
Scadenza: 2029-06-26
Importo max: 50.114 EUR
Paese: US
Descrizione
PROJECT SUMMARY:
Methamphetamine use disorder (MUD) is characterized as a cluster of symptoms associated with chronic
use of methamphetamine (METH) despite negative consequences. The number of overdose deaths related to
METH use is on the rise. However, there are no FDA approved MUD therapeutics, making generation of novel
pharmacotherapies critical. METH functions primarily as a dopamine (DA) releaser and produces its reinforcing
effects by elevating DA levels in the mesolimbic DA system, which consists of projections from the ventral
tegmental area (VTA) to the nucleus accumbens (NAc). Yet, chronic METH use leads to hypodopaminergia
(hypoDA), a state characterized by reduced DA system function that is theorized to promote negative affective
states and perpetuate METH use. Therefore, a therapeutic strategy for MUD is to target proteins that facilitate
DA transmission, as this could counteract METH-induced DA deficits. One such protein is the synaptic vesicle
protein synaptogyrin-3 (Syngr3). The exact mechanisms of Syngr3 activity in DA neurons are unknown, but it is
hypothesized to have a role in (1) DA release by regulating exocytosis and vesicle mobility and (2) DA uptake
via interactions with the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT-2). Recent
studies in our lab found that viral overexpression of Syngr3 in VTA DA neurons (Syngr3 OE) decreased
cocaine (COC) self-administration (SA) and protected against COC-induced deficits in DA transmission. Given
the protective role of Syngr3 against COC taking, we wanted to probe whether the findings would translate to
METH. The initial hypothesis was that Syngr3 would play a similar protective role; however, preliminary data
indicate that Syngr3 OE rats may show increased METH SA behaviors relative to controls. We postulate that
the opposing results are because METH produces its effects in part by inducing DAT-mediated DA efflux, a
process that Syngr3 could enhance by organizing presynaptic release machinery. Further investigation is
needed to gain a deeper insight into Syngr3’s role in modulating MUD-related behaviors and the effects of
METH on the DA system. The central hypothesis of this study is that METH taking and METH-induced
deficits in DA transmission are facilitated by Syngr3 function in VTA DA neurons. Viral overexpression of
Syngr3 in VTA DA neurons will be used to assess the functional consequences of Syngr3 activity. This will
ultimately aid in the development of a deeper understanding of Syngr3’s role in regulating DA homeostasis,
which can be used as a foundation to guide the development of novel therapeutics for MUD in the future.
Istituzione: WAKE FOREST UNIVERSITY HEALTH SCIENCES
PI: Kathryn R. Beard
Progetto: 1F31DA066221-01
Settori: National Institute on Drug Abuse
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